Le syndrome d'apnée du sommeil (SAS) est une maladie multifactorielle caractérisée par des épisodes récurrents de pauses respiratoires ou des réductions significatives de l'amplitude respiratoire pendant le sommeil. Ces épisodes peuvent provoquer des réactions cardiorespiratoires aiguës; délétères à long terme. Plusieurs thérapies ont été proposées, étant la pression positive continue des voies respiratoires (CPAP) le traitement de référence. Malgré ces excellents résultats chez les patients symptomatiques, le taux de refus initial est de 15% et une adhésion à long terme est difficile à atteindre. Par conséquent, le développement de méthodes de traitement non invasives, avec une meilleure acceptabilité, reste d’une importance majeure. Dans ce contexte, l’hypothèse qui sous-tend ce travail est qu’une stimulation kinesthésique contrôlée, délivrée au cours de la phase précoce de l’apnée, peut réduire la durée des événements respiratoires et, par la suite, limiter les désaturations d’oxygène associées, par une activation contrôlée du réflexe de sursaut. La première partie de ce manuscrit est consacrée à la description d'un nouveau système (PASITHEA) de surveillance en temps réel et de neuromodulation thérapeutique, qui fonctionne comme un dispositif polyvalent de diagnostic et de traitement de SAS par stimulation kinesthésique. Les principales contributions de cette thèse se concentrent sur les aspects du traitement du signal et du contrôle de ce système, ainsi que sur l'électronique associée. Une autre contribution est liée à l'évaluation de ces méthodes et dispositifs par des protocoles cliniques spécifiques. Dans une deuxième partie, nous proposons une première méthode de contrôle On/Off optimale pour délivrer la stimulation, en utilisant comme variable de contrôle la sortie d'un détecteur d'événements respiratoires en temps réel. Lors de la détection d'un événement, une stratégie de stimulation unique avec amplitude de stimulation constante est appliquée, cette dernière a été mise en œuvre dans le cadre d'un premier protocole clinique dédié à l'évaluation de la réponse du patient au traitement. Les résultats ont montré que 75% des patients répondaient correctement au traitement en termes de durées des épisodes respiratoires. De plus, des diminutions significatives de la variabilité du SaO2 ont également été constatées lors de la mise en œuvre d'une nouvelle méthode d'analyse aiguë. Puisque nous avons supposé qu'une sélection inappropriée des patients pourrait expliquer l'absence de réponse observée chez 25% des patients. Nous avons proposé une méthode pour différencier les patients qui pourraient bénéficier de cette thérapie, basée sur l'estimation d'indices de variabilité cardiaque. Les résultats de ces analyses ont montré que l'efficacité de cette thérapie semble corrélée à un système nerveux autonome fonctionnel. Enfin, une méthode améliorée de contrôle en boucle fermée, intégrant des correcteurs proportionnels-dérivés (PD) couplés et simultanés a été proposée afin de modifier de façon adaptative l’amplitude de stimulation kinesthésique délivrée au patient par le système thérapeutique, en utilisant comme variables de contrôle des signaux physiologiques enregistrés en temps réel. Un deuxième protocole clinique visant à valider l'algorithme de contrôle de la stimulation kinesthésique adaptative spécifique au patient a été initié. Plusieurs améliorations ont été effectuées à la première version du système afin de permettre l'intégration du contrôleur proposé. Les résultats préliminaires de cette étude ont validé le fonctionnement de notre contrôleur et ont montré que notre système était capable de fournir une stimulation kinesthésique adaptative en fonction des réponses propres au patient. Une autre phase de cette étude, mettant en œuvre le contrôleur avec un ensemble des paramètres de contrôle présélectionnés, est actuellement en cours. / Sleep apnea syndrome (SAS) is a multifactorial disease characterized by recurrent episodes of breathing pauses or significant reductions in respiratory amplitude during sleep. These episodes may provoke acute cardiorespiratory responses along with alterations of the sleep structure, which may be deleterious in the long term. Several therapies have been proposed for the treatment of SAS, being continuous positive airway pressure the gold standard treatment. Despite its excellent results in symptomatic patients, there is a 15% initial refusal rate and long term adherence is difficult to achieve in minimally symptomatic patients. Therefore, the development of non-invasive SAS treatment methods, with improved acceptability, is of major importance. The objective of this PhD thesis is to propose new signal processing and control methods of non-invasive neuromodulation for the treatment of SAS. The hypothesis underlying this work is that bursts of kinesthetic stimulation delivered during the early phase of apneas or hypopneas may elicit a controlled startle response that can activate sub-cortical centers controlling upper airways muscles and the autonomic nervous system, stopping respiratory events without generating a cortical arousal. In this context, the first part of this manuscript is dedicated to the description of a novel real-time monitoring and therapeutic neuromodulation system, which functions as a multi-purpose device for SAS diagnosis and treatment through kinesthetic stimulation. This system has been developed in the framework of an ANR TecSan project led by our laboratory, with the participation of Sorin CRM SAS. The main contributions in this thesis are focused on the signal processing and control aspects of this system, as well as the electronics associated. Another contribution is related to the evaluation of these methods and devices through specific clinical protocols. In a second part, we propose a first optimal On/Off control method for delivering kinesthetic stimulation, using as control variable the output of a real-time respiratory event detector. A unique stimulation strategy where a constant stimulation amplitude is applied upon event detention was implemented in a first clinical protocol, dedicated to assessing the patient response to therapy. Results showed that 75% of the patients responded correctly to therapy, showing statistically significant reductions in respiratory event durations. Also, significant decreases in the SaO2 variability were also found when implementing a novel acute analysis method. Since we hypothesized that inappropriate patient selection could explain the observed lack of response in 25% of patients, we proposed a method to differentiate patients who could benefit from this therapy based on the estimation of complexity-based indexes of heart rate variability. Results of these analyses showed that the effectiveness of this therapy seems correlated to a functional autonomic nervous system. Finally, an improved closed-loop control method integrating concurrent, coupled proportional-derivative (PD) controllers in order to adaptively change the kinesthetic stimulation was proposed. It uses as control variables three physiological signals recorded in real-time: Nasal pressure, oxygen saturation and the electrocardiogram signal. A second clinical protocol with the main objective of validating the control algorithm for patient-specific adaptive kinesthetic stimulation was launched. Several improvements to the first version of the system were developed to allow the integration of the proposed controller. Preliminary results from the first phase of this study validated the proposed controller operation and showed that the controller was able to provide adaptive kinesthetic stimulation in function of the patient-specific responses. A second phase of this study implementing the proposed controller and the set of the selected control parameters from the first phase is currently ongoing.

Thioredoxin is a small ubiquitous oxido-reductase found in all species. The highly conserved active site, which facilitates thioredoxins redox activity, contains two redox active cysteine residues. Thioredoxin has numerous protein substrates to which it donates H+ ions and it can also function as a free radical scavenger. Through these activities thioredoxin is able to influence the redox state of not only its protein targets, but also the entire cellular environment. Thioredoxin has been implicated in many biological functions, and one mechanism by which it influences these functions is through interactions with a number of transcription factors including NF-kappa-B and p53. Thioredoxin also has numerous extracellular biological roles. It has been shown that thioredoxin is actively secreted from a number of normal and transformed cell lines including fibroblasts and activated B and T cells. This study investigates the role of thioredoxin in embryonic implantation and cancer cell metastasis, two physiological functions which rely on the same basic processes. Thioredoxin expression has previously been shown to be increased in many cancers. However it has not yet been established whether this increase is a causative or a side effect of the cancerous phenotype. Similarly thioredoxin expression has previously been shown to be increased during different phases of the oestrus cycle and pregnancy. This thesis describes the role of thioredoxin in embryonic implantation using a marmoset model. A thioredoxin cDNA was isolated and subsequently sequenced. Preliminary antibody experiments indicated that the anti human thioredoxin monoclonal antibodies available in our laboratory would recognise marmoset thioredoxin. Subsequently immunocytochemistry using anti human thioredoxin antibodies was carried out on sectioned marmoset uterus and embryonic tissue. The results indicated that thioredoxin is expressed by cells at the embryonic-maternal interface of early implantation sites. Further studies demonstrated that thioredoxin is also expressed and secreted by cultured blastocysts in vitro. This thesis also describes the role of thioredoxin in cancer cell metastasis. Results of this study indicate that thioredoxin is actively involved in facilitating the invasive phenotype of breast cancer cells. The two cell lines utilised were MCF-7, a well differentiated, relatively non-invasive breast cancer cell line; and MDA-MB-231, a poorly differentiated, highly invasive breast cancer cell line. The cell lines were transfected with thioredoxin sense, antisense and 1SS (encodes thioredoxin with both active cysteine residues mutated to serine residues and is thus redox inactive) constructs. The results demonstrate that when endogenous thioredoxin levels are increased, i.e. transfected with a sense thioredoxin construct, the invasive breast cancer cell line MDA-MB-231 becomes more invasive, conversely when endogenous levels are decreased, i.e. transfected with antisense or 1SS constructs, the invasive capacity of these cells decreases. However, when the endogenous level of thioredoxin was manipulated in the relatively non-invasive cell line MCF-7 very little effect was observed. Results also indicate that thioredoxin has the ability to act as a chemoattractant for actively invading breast cancer cells. Both of these functions appear to be dependent on thioredoxin's redox activity. Additional studies described in this thesis have shown that thioredoxin is involved in the regulation of Sp1 in vitro. Sp1 is a transcription factor known to regulate the transcription of a number of genes whose products are intimately involved in the invasive phenotype. The results in this study suggest that Sp1 DNA binding is regulated by thioredoxin such that when reduced by the enzyme its binding to DNA is facilitated. Results also indicate that Sp1 may regulate the transcription of thioredoxin by binding to Sp1 sites within the thioredoxin promoter.

Graduation date: 1998

Thèse doctorat : Automatique Industrielle : Villeurbanne, INSA : 2005. / Thèse rédigée en anglais. Résumé étendu en français. Titre provenant de l'écran-titre. Bibliogr. p. 155-167.

Woody plant encroachment, that is, a substantial increase in the abundance of woody plants in a grassland or savanna, occurs in many parts of the world. It often has large effects on plant and animal populations and communities and on ecosystem properties and processes. However, little is known about the dynamics of woody plant encroachment and how these are affected by soils, by topography, and by the spatial pattern of the vegetation. Encroachment in turn can affect the spatial pattern of the vegetation. Using data from historical aerial photographs, I measured changes in woody plant cover and constructed, parameterized and compared a set of dynamic models of woody plant encroachment in central Texas savannas. These models predicted final woody cover from initial woody cover and the initial spatial configuration of woody plants. Then I incorporated soil and topography into these models to determine their effects. Finally, I examined the effects of encroachment on the spatial pattern of the vegetation. Incorporating negative density dependence in our models improved their fit, demonstrating that encroachment is density-dependent. A function that predicted the formation of new woody patches from a density-independent seed supply also improved the models' performance. The improvement in the models that resulted from incorporating the total length of woody-herbaceous edges confirmed that encroachment in this system occurs in part by the outward expansion of woody patches. The spatial pattern of the vegetation changed during woody plant encroachment. Spatial pattern (measured as degree of fragmentation) often had a non-linear relationship with cover. Furthermore, the spatial heterogeneity in fragmentation, that is, plot-to-plot variation in the degree of fragmentation, also changed during encroachment. Topography and soil type had, in general, little effect the dynamics of woody plant encroachment. Therefore, a relatively simple model of woody plant encroachment provided good predictions of woody cover at the end of the time periods. Other systems experiencing woody plant encroachment, forest succession, or invasion by non-native plants could be modeled using the same approach. / text

Kommt es zu einer akuten respiratorischen Insuffizienz, stellt die Beatmung einen wichtigen Eckpfeiler der Therapie dar. Da eine invasive Beatmung über einen endotrachealen Tubus mit Risiken verbunden ist, sollte wann immer möglich, eine nicht-invasive Beatmung eingesetzt werden. Neben den absoluten Kontraindikationen limitieren Undichtigkeit, Ulzerationen im Gesichtsbereich und ein schlechter Tragekomfort die Praktikabilität der Gesichtsmasken. Ziel dieser Arbeit war die Evaluation eines neuartigen Beatmungshelms in einem Lungenmodell und einer Probandenstudie im Hinblick auf Beatmungsparameter (Beatmungsdruck, AZV, AMV, PEEP) Resistance, Compliance, Delay-Zeiten, CO2, SpO2, Triggerzeit und Komfort. Es zeigte sich, dass eine Steigerung des PEEP auf 8 mbar zu einer signifikanten Reduktion der DelayTrigger und DelayPeep-Zeiten führte. Höhere PEEP-Werte gingen hingegen mit einer zunehmenden Leckage und Gefahr einer Desynchronität zwischen Proband und Ventilator einher. Eine zusätzliche Druckunterstützung konnte das AMVLunge signifikant steigern, was zu einem Abfall der CO2-Konzentration sowohl in der transkutanen Messung als auch im Helm führte. Problematisch zeigte sich aufgrund der Compliance des Helms, dass ein hoher Anteil des AMV zum Druckaufbau im Helm verloren geht. Dieser Effekt war abhängig von PEEP, ASB sowie Compliance und Resistance der Lunge. Der Beatmungshelm ist als eine gute Alternative zu betrachten, wenn eine Aufrecherhaltung eines PEEPs im Vordergrund steht, wie etwa bei einer Oxygenierungstörung bei Parenchymversagen.

Invasive alien species (IAS) pose a serious threat to ecosystems and societies worldwide. Local ecological knowledge (LEK) is increasingly valued as a means of understanding environmental issues; however, its application in the context of IAS research has been limited. The overall objective of this study was to document the LEK of farmers and Weed Supervisors to gain insight into a recent IAS, Odontites serotina. I conducted semi-structured interviews with farmers and Weed Supervisors with O. serotina management experience. Results indicated that the socio-economic impacts for farmers were severe in affected rural communities. However, participants had developed promising control techniques, including the application of compost mulch. I used this LEK as well as data on species occurrence, environmental variables, and measures of propagule pressure to forecast the potential distribution of O. serotina across Manitoba. The risk map generated will be useful for guiding future monitoring and public outreach efforts.

Invasive alien species (IAS) pose a serious threat to ecosystems and societies worldwide. Local ecological knowledge (LEK) is increasingly valued as a means of understanding environmental issues; however, its application in the context of IAS research has been limited. The overall objective of this study was to document the LEK of farmers and Weed Supervisors to gain insight into a recent IAS, Odontites serotina. I conducted semi-structured interviews with farmers and Weed Supervisors with O. serotina management experience. Results indicated that the socio-economic impacts for farmers were severe in affected rural communities. However, participants had developed promising control techniques, including the application of compost mulch. I used this LEK as well as data on species occurrence, environmental variables, and measures of propagule pressure to forecast the potential distribution of O. serotina across Manitoba. The risk map generated will be useful for guiding future monitoring and public outreach efforts.

Thesis (Ph.D.)--University of Wollongong, School of Biological Sciences. / Typescript. Includes bibliographical references: leaf 161-203.

Thesis (Ph.D.)--Mississippi State University. Department of Biological Sciences. / Title from title screen. Includes bibliographical references.